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. 2018 Dec 21:16:34.
doi: 10.1186/s12959-018-0188-y. eCollection 2018.

Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Anthonie W A Lensing  1 , Christoph Male  2 , Guy Young  3 , Dagmar Kubitza  1 , Gili Kenet  4 , M Patricia Massicotte  5 , Anthony Chan  6 , Angelo C Molinari  7 , Ulrike Nowak-Goettl  8 , Ákos F Pap  1 , Ivet Adalbo  1 , William T Smith  1 , Amy Mason  1 , Kirstin Thelen  1 , Scott D Berkowitz  1 , Mark Crowther  9 , Stephan Schmidt  10 , Victoria Price  11 , Martin H Prins  12 , Paul Monagle  13
Affiliations

Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Anthonie W A Lensing et al. Thromb J. .

Abstract

Background: Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily.

Methods: EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0-18 years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months.

Conclusions: EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.

Trial registration: Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

Keywords: Anticoagulation; Bodyweight-adjusted dosing; Pediatric patients; Rivaroxaban; Venous thromboembolism.

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Conflict of interest statement

Study sponsors and investigators agreed to abide by Good Clinical Practice guidelines and under the guiding principles detailed in the Declaration of Helsinki, and in accordance with any applicable local law(s) and regulation(s). Documented approval from appropriate Independent Ethics Committees/Institutional Review Boards was obtained for all participating centers/countries prior to the start of the study, according to Good Clinical Practice, local laws, regulations and organizations. As a requirement for participation, informed consent will be asked from the parent(s)/legal guardian(s) and, if appropriate as determined by local regulation, age and individual child capability, child assent will be sought, according to country-specific regulations.Not applicable.AWAL, DK, AFP, IA, WTS, AM, and KT are employees of Bayer AG. CM has received consulting fees from Bayer and Bristol-Myers Squibb, and lecture fees from Bayer. GK has received research funding from Pfizer and receives consulting and lecture fees from Daichi Sankyo. MPM has received consulting fees from Bayer. AC has received consulting fees from Bayer, Daiichi Sankyo, and Pfizer/Bristol-Myers Squibb. ACM has received consulting fees from Bayer, CSL Behring, Kedrion, NovoNordisk, Pfizer, Shire, and SOBI. UNG has received consulting fees from Bayer, Boehringer, Octapharma, LFB, and SOBI. MG has received consulting fees from Bayer, Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Daiichi Sankyo, and lecture fees from Pfizer, Alexion, and CSL Behring. SS has received consulting fees from Bayer. MHP has received consulting fees from Bayer, Pfizer, and Daiichi Sankyo. GY, VP, and PM declare no competing financial interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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